Project Summary Giant cell pneumonitis (GCP) is a collection of fatal chronic diseases, including hard metal lung disease, virus-associated GCP and non-hard metal, non-infectious GCP. Regardless of the etiology, GCP is characterized by the presence of alveolar macrophage-derived multinucleate giant cells (MGCs) that together with other immune infiltrates obstruct alveolar spaces and cause lung failure. Little is known on the pathogenesis of GCP, which is largely due to lack of appropriate animal models, and there is no effective treatment, presenting a critical knowledge gap. In this proposal, we will close an aspect of this knowledge gap by using a unique animal model of GCP we recently developed to investigate the immunological mechanisms that lead to this fatal disease. Hard metal (such as cobalt) workers had elevated levels of serum IgE, a CD4+ T helper (TH) 2 cell-dependent antibody isotype, and patients with hard metal GCP contained increased numbers of T cells in their bronchoalveolar lavage fluids (BALFs), implicating a potential role of T cells in the pathology of GCP. However, it is entirely unclear how dysregulation of TH cells causes MGC formation, resulting in the development of GCP. Our long-term goal is to dissect the mechanisms underlying the pathogenesis of GCP; the discoveries may lead to novel therapeutic options. The scientific premise of this proposal is strongly supported by our preliminary studies that CIS, a member of the suppressor of the cytokine signaling (SOCS) family, is required to suppress GCP, which is likely via a T cell-dependent manner; Cis-deficiency in mice leads to formation and accumulation of MGCs with increased numbers of TH cells in the lungs and causes severe obstruction of alveoli, leading to even death. Our central hypothesis is that CIS inhibits MGC formation via restricting TH cell responses, therefore preventing GCP. The Specific Aims are: Aim 1. Determine the TH cell-intrinsic role of CIS in the development of GCP. Aim 2. Delineate the mechanism underlying the suppressive function of CIS in GCP, especially hard metal lung disease.